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Antimicrobial Agents and Chemotherapy, November 1998, p. 2989-2995, Vol. 42, No. 11
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Intracellular Nucleotides of (-)-2',3'-Deoxy-3'-Thiacytidine in Peripheral Blood Mononuclear Cells of a Patient Infected with Human Immunodeficiency Virus

Caroline Solas, Yu-Feng Li, Meng-Yu Xie, Jean-Pierre Sommadossi,* and Xiao-Jian Zhou

Department of Clinical Pharmacology, The Liver Center, Center for AIDS Research, University of Alabama at Birmingham, Birmingham, Alabama 35294-0019

Received 19 June 1998/Accepted 12 August 1998

An analytical methodology was developed to quantitate the intracellular nucleotides including mono-, di-, and triphosphates and the diphosphocholine derivative of (-)-2',3'-deoxy-3'-thiacytidine (3TC) in human peripheral blood mononuclear cells (PBMCs). The procedure includes the resolution of 3TC nucleotides by solid-phase extraction (SPE) on an anion-exchange cartridge, with subsequent enzyme digestion of the resulting phosphates to the parent drug that is ultimately quantitated by high-performance liquid chromatography with UV detection (HPLC-UV). Validation was performed with PBMCs from healthy donors exposed to [3H]3TC, leading to the formation of intracellular nucleotides that were quantitated by anion-exchange HPLC with radioactive detection (HPLC-RA). These nucleotide levels served as reference values and were used for cross-validation with data obtained by HPLC-UV. An excellent correlation was established between the results obtained by HPLC-RA and those obtained by HPLC-UV, with a slope of the regression lines close to unity and intercepts near nullity as well as a correlation coefficient close to unity for all 3TC phosphates. The assay was characterized by a limit of quantitation below 1 ng (amount on column) with a precision (percentage of coefficient of variation of repeated measurement) ranging from 0.8 to 18.1% and an accuracy (deviation of the amount determined by HPLC-UV from the nominal reference value) varying from -14.8 to 19.4%. This methodology was successfully applied to determine the quantity of 3TC nucleotides in PBMCs of a patient infected with human immunodeficiency virus after oral administration of 3TC and stavudine.

* Corresponding author. Mailing address: Department of Clinical Pharmacology, University of Alabama at Birmingham, Box 600, Volker Hall G019, University Station, Birmingham, AL 35294. Phone: (205) 934-8226. Fax: (205) 975-4871. E-mail: Jean-Pierre.Sommadossi{at}CCC.UAB.EDU.

Antimicrobial Agents and Chemotherapy, November 1998, p. 2989-2995, Vol. 42, No. 11
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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